Disparities in prostate cancer (Pca) are caused by complex interactions of genetic susceptibility, individual risk factors, and environmental factors. Pca is the second leading cause of death among all men; however African American (AA) men have the highest mortality rate of Pca of any racial/ethnic group in the U.S. This difference in mortality accounts for 44% of the overall cancer mortality disparity between AA and European-American (EA) men. Thus, there is a critical need to explore the etiologic pathways that contribute to this disparity. Unfortunately, the only well-established risk factors (age, race and family history) for Pca are non-modifiable. However recent studies have found low levels of vitamin D have been associated with increased Pca risk, and treatment with vitamin D has reduced Pca disease progression in multiple studies. These studies support the hypothesis that vitamin D deficiency increases the risk of Pca and that vitamin D is a potential chemopreventive and therapeutic agent. Although genetic and environmental factors including common low penetrant alleles, diet, body mass index (BMI), and vitamin D levels may affect risk, their significance and multiple joint effects are unclear. Extensive data exists in support of a critical role for Vitamin D3 [25(OH) vitamin D] on Pca risk. However, it is difficult to determine its importance mainly because Vitamin D is synthesized in the skin, and serum levels are strongly influenced by skin color, genetic ancestry, age, BMI, and environmental factors such as sunlight exposure and diet. The goal of this project is to explore the effects of serum Vitamin D, UVR exposure, skin color, age, BMI, and genes involved in Vitamin D synthesis, metabolism and signaling on Pca and aggressive Pca risk in a study of 2,000 AA and 2,000 EA men. Men aged 40-79 will be recruited from a consortium of Chicago hospitals including, the University Illinois a Chicago Hospital System, University of Chicago Medical Center, Northwestern Memorial Hospital, John H. Stroger Cook County Hospital, and the Jesse Brown Veteran Affairs Medical Center. This project will improve our understanding of the role Vitamin D plays on prostate cancer susceptibility, specifically among African Americans, and if lower vitamin D levels in AAs account for a portion of the disparity in Pca incidence and mortality between AAs and EAs. More importantly, given that UVR and diet are general environmental exposures that can be easily modified, understanding their impact may have broad health implications. PUBLIC HEALTH RELEVANCE: Vitamin D has been shown to induce differentiation of prostate cells and to inhibit growth and induce apoptosis in prostate cancer cell lines. There has been epidemiologic evidence linking vitamin D status to breast, colon and prostate cancer. Prospective studies have been lacking and among the literature there have been inconclusive results. Notably, these studies are lacking in numbers of men of African ancestry who are likely to have aggressive prostate cancer and to be more vitamin D deficient. Also the studies fail to look at the interaction of vitamin D level, sun exposure, skin color, and genetic variation in genes in the vitamin D synthesis and metabolism pathway. Here we will propose a prospective study of serum vitamin D (25-OH D) levels and prostate cancer risk among African American and European American men aged 40-79. The study will be conducted at five Chicago area institutions, the University Illinois at Chicago Hospital System, University of Chicago Medical Center, Northwestern Memorial Hospital, John H. Stroger Cook County Hospital, and the Jesse Brown Veteran Affairs Medical Center in Chicago.